A particularly important design we are now considering involves a tetrad structure, with one affected and one unaffected offspring, in addition to the two parents. This design has been implemented in the Two Sister Study (funded in part by Susan G. Komen for the Cure), which is assessing the joint role of genetic and environmental risk factors in young-onset (under age 50) breast cancer. The discordant sib pair allows estimation of effects of exposures, while the embedded case-parent triad allows detection of haplotypes that confer either protection or risk. The tetrad analyzed together should provide a powerful design for assessing gene-by-environment interaction. We have been working on developing and evaluating methods for use with the tetrad design. We have begun to explore possible interactions between the genetic risk score and known risk factors. The availability of an algorithm for simulating genomic data with realistic linkage structure provides a laboratory for development of new methods for assessing both GxGxG interactions and GxGxE interactions.